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2.
PLoS One ; 16(4): e0250102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33901219

RESUMO

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Estudos de Coortes , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neoplasias Ovarianas , Prognóstico , Fatores de Risco , Singapura/epidemiologia , Inquéritos e Questionários
3.
Breast Cancer Res Treat ; 188(3): 713-727, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33768416

RESUMO

BACKGROUND: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants. METHODS: Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium. RESULTS: Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time. CONCLUSIONS: Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.


Assuntos
Neoplasias da Mama , Metilação de DNA , Adolescente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
4.
Theranostics ; 11(3): 1115-1128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391524

RESUMO

BReast tumor Kinase (BRK, also known as PTK6) is a non-receptor tyrosine kinase that is highly expressed in breast carcinomas while having low expression in the normal mammary gland, which hints at the oncogenic nature of this kinase in breast cancer. In the past twenty-six years since the discovery of BRK, an increasing number of studies have strived to understand the cellular roles of BRK in breast cancer. Since then, BRK has been found both in vitro and in vivo to activate a multitude of oncoproteins to promote cell proliferation, metastasis, and cancer development. The compelling evidence concerning the oncogenic roles of BRK has also led, since then, to the rapid and exponential development of inhibitors against BRK. This review highlights recent advances in BRK biology in contributing to the "hallmarks of cancer", as well as BRK's therapeutic significance. Importantly, this review consolidates all known inhibitors of BRK activity and highlights the connection between drug action and BRK-mediated effects. Despite the volume of inhibitors designed against BRK, none have progressed into clinical phase. Understanding the successes and challenges of these inhibitor developments are crucial for the future improvements of new inhibitors that can be clinically relevant.


Assuntos
Neoplasias da Mama/genética , Proteínas de Neoplasias/genética , Proteínas Tirosina Quinases/genética , Animais , Neoplasias da Mama/patologia , Proliferação de Células/genética , Feminino , Humanos , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Oncogenes/genética
5.
Eur Radiol ; 31(5): 2657-2666, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33125555

RESUMO

OBJECTIVE: To develop a risk predictor model in evaluation of tomosynthesis-detected architectural distortion (AD) based on characteristics of contrast-enhanced digital mammography (CEDM). METHODS: Ninety-four AD lesions on CEDM in combination with tomosynthesis were retrospectively reviewed from 92 consecutive women (mean age, 52.4 years ± 7.9) with abnormal diagnostic or screening mammography. CEDM results were correlated with histology of ADs using cross-tabulation for statistical analysis. Predictors for risk of malignancy from CEDM characteristics (background parenchyma enhancement, degree of AD enhancement, enhancing morphology, size of enhancement, and enhancing spiculations) and patient's age were evaluated using logistic regression. We propose a sum score, termed AD score (ADS), for risk stratification and corresponding suggested BI-RADS category. RESULTS: Thirty-three of ninety-four (35.1%) of detected AD lesions were malignant. The sensitivity, specificity, PPV, and NPV of CEDM in evaluation of malignant AD are 100%, 42.6%, 48.5%, and 100%, respectively. Absence of AD enhancement on CEDM is highly indicative of no underlying malignancy. On multivariate analysis, the predictors on CEDM with statistical significance are (1) marked intensity of AD enhancement (OR, 22.6; 95%CI 3.1, 166.6; p = .002); and (2) presence of enhancing spiculations (OR, 9.1; 95%CI 2.2, 36.5; p = .002). A prediction model whose scores (ADS) given by ranking of OR of all predictors with AUC of 0.934 and Brier score of 0.0956 was developed. CONCLUSION: ADS-based lesion characterization on CEDM enables risk assessment of tomosynthesis-detected AD lesions. KEY POINTS: • Architecture distortions presenting with marked enhancement intensity and presence of enhancing spiculations are highly associated with risk of malignancy. • Absence of architecture distortion enhancement in minimal or mild background parenchyma enhancement on CEDM indicates low risk of breast malignancy (NPV = 100%).


Assuntos
Neoplasias da Mama , Mamografia , Neoplasias da Mama/diagnóstico por imagem , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Intensificação de Imagem Radiográfica , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade
6.
Nat Commun ; 11(1): 3833, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737321

RESUMO

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Ásia/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Risco
7.
Photoacoustics ; 19: 100164, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32420026

RESUMO

In this pilot study, we tested an ultrasound-guided optoacoustic tomography (US-OT) two-dimensional (2D) array scanner to understand the optoacoustic patterns of excised breastconserving surgery (BCS) specimens. We imaged 14 BCS specimens containing malignant tumors at eight wavelengths spanning 700-1100 nm. Spectral unmixing across multiple wavelengths allowed for visualizing major intrinsic chromophores in the breast tissue including hemoglobin and lipid up to a depth of 7 mm. We identified less/no lipid signals within the tumor and intense deoxy-hemoglobin (Hb) signals on the rim of the tumor as unique characteristics of malignant tumors in comparison to no tumor region. We also observed continuous broad lipid signals as features of negative margins and compromised lipid signals interrupted by vasculature as features of positive margins. These differentiating patterns can form the basis of US-OT to be explored as an alternate, fast and efficient intraoperative method for evaluation of tumor resection margins.

8.
Transl Oncol ; 13(2): 254-261, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31869750

RESUMO

PURPOSE: To determine the accuracy of a handheld ultrasound-guided optoacoustic tomography (US-OT) probe developed for human deep-tissue imaging in ex vivo assessment of tumor margins postlumpectomy. METHODS: A custom-built two-dimensional (2D) US-OT-handheld probe was used to scan 15 lumpectomy breast specimens. Optoacoustic signals acquired at multiple wavelengths between 700 and 1100 nm were reconstructed using model linear algorithm, followed by spectral unmixing for lipid and deoxyhemoglobin (Hb). Distribution maps of lipid and Hb on the anterior, posterior, superior, inferior, medial, and lateral margins of the specimens were inspected for margin involvement, and results were correlated with histopathologic findings. The agreement in tumor margin assessment between US-OT and histopathology was determined using the Bland-Altman plot. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of margin assessment using US-OT were calculated. RESULTS: Ninety margins (6 × 15 specimens) were assessed. The US-OT probe resolved blood vessels and lipid up to a depth of 6 mm. Negative and positive margins were discriminated by marked differences in the distribution patterns of lipid and Hb. US-OT assessments were concordant with histopathologic findings in 87 of 89 margins assessed (one margin was uninterpretable and excluded), with diagnostic accuracy of 97.9% (kappa = 0.79). The sensitivity, specificity, PPV, and NPV were 100% (4/4), 97.6% (83/85), 66.7% (4/6), and 100% (83/83), respectively. CONCLUSION: US-OT was capable of providing distribution maps of lipid and Hb in lumpectomy specimens that predicted tumor margins with high sensitivity and specificity, making it a potential tool for intraoperative tumor margin assessment.

9.
Nat Biomed Eng ; 3(9): 684-694, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31285580

RESUMO

Massively parallel DNA sequencing is established, yet high-throughput protein profiling remains challenging. Here, we report a barcoding approach that leverages the combinatorial sequence content and the configurational programmability of DNA nanostructures for high-throughput multiplexed profiling of the subcellular expression and distribution of proteins in whole cells. The barcodes are formed by in situ hybridization of tetrahedral DNA nanostructures and short DNA sequences conjugated with protein-targeting antibodies, and by nanostructure-assisted ligation (either enzymatic or chemical) of the nanostructures and exogenous DNA sequences bound to nanoparticles of different sizes (which cause these localization sequences to differentially distribute across subcellular compartments). Compared with linear DNA barcoding, the nanostructured barcodes enhance the signal by more than 100-fold. By implementing the barcoding approach on a microfluidic device for the analysis of rare patient samples, we show that molecular subtypes of breast cancer can be accurately classified and that subcellular spatial markers of disease aggressiveness can be identified.


Assuntos
Código de Barras de DNA Taxonômico/métodos , DNA/química , DNA/classificação , Perfilação da Expressão Gênica/métodos , Nanoestruturas , Anticorpos/imunologia , Anticorpos/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Código de Barras de DNA Taxonômico/instrumentação , Humanos , Cinética , Dispositivos Lab-On-A-Chip , Proteínas , Coloração e Rotulagem
12.
PLoS One ; 13(8): e0201606, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30161160

RESUMO

PURPOSE: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. EXPERIMENTAL DESIGN: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. RESULTS: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs. CONCLUSION: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Marcadores Genéticos , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Cromossomos Humanos/genética , Feminino , Marcadores Genéticos/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Análise de Sequência de DNA , Tamoxifeno/farmacologia , Resultado do Tratamento
13.
Waste Manag ; 75: 174-180, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29395734

RESUMO

Better treatment and management strategies than landfilling are needed to address the large quantities of unrecycled plastic waste generated by daily human activities. Waste-to-energy conversion is an ideal benchmark for developing future large-scale waste management technologies. The present study explores a new approach for producing energetic materials by converting inert plastic waste into energy (thermal and mechanical energies) via a light-controlled process through the simple chemical activation of plastic waste, including polyethylene, polypropylene, and polyvinyl chloride. The inert and non-polar polymer surfaces of the plastics were modified by generating a number of sulfonic groups (SO3-) using chlorosulfuric acid, followed by grafting of Fe(III) catalyst onto the polymer chains to obtain activated polymer. Elemental analyses of these activated materials showed that the carbon-to-sulfur ratio ranged from 3:1 to 5:1. The FTIR spectra indicated the presence of CC bonds (vC=C: 1615-1630 cm-1) and SO bonds (vS=O: 1151-1167 cm-1) in the activated polymers after chemical reaction. These activated materials were energetic, as light could be used to convert them into thermal (1800-3200 J/g) and mechanical energies (380-560 kPa/g) using hydrogen peroxide as the oxidant under ambient conditions within 1 h.


Assuntos
Conservação de Recursos Energéticos , Plásticos , Reciclagem , Gerenciamento de Resíduos , Compostos Férricos , Polietileno , Polipropilenos
14.
Clin Cancer Res ; 23(8): 2019-2026, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-27797974

RESUMO

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019-26. ©2016 AACR.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Resultado do Tratamento
15.
Onco Targets Ther ; 9: 5561-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27660474

RESUMO

INTRODUCTION: Accelerated partial breast irradiation (APBI) using the multicatheter method has excellent cosmesis and low rates of long-term toxicity. However, there are few studies looking at the feasibility of this procedure and the outcomes in an Asian population. This study aims to look at outcomes at our hospital. METHODS: We identified 121 patients treated with APBI at our center between 2008 and 2014. The median follow-up for our patient group was 30 months (range 3.7-66.5). The prescribed dose per fraction was 3.4 Gy in 10 fractions. In this study population, 71% of the patients were Chinese while 15% (n=19) were of other Asian ethnicity. RESULTS: In this study, the median breast volume was 850 cc (range 216-2,108) with 59.5% (n=72) patients with a breast volume of <1,000 cc. The average planning target volume was 134 cc (range 28-324). The number of catheters used ranged from 8 to 25 with an average of 18 catheters used per patient. We achieved an average dose homogeneity index of 0.76 in our patients. The average D90(%) was 105% and the average D90(Gy) was 3.6 Gy per fraction. The median volume receiving 100% of the prescribed dose (V100) was 161.7 cc (range 33.9-330.1), 150% of the prescribed dose (V150) and 200% of the prescribed dose (V200) was 39.4 cc (range 14.6-69.6) and 14.72 cc (range 6.48-22.25), respectively. Our dosimetric outcomes were excellent even in patients with breast volume under 1,000 cc. There were no cases of grade 3 skin toxicity or acute pneumonitis. Two patients had a postoperative infection and two patients had fat necrosis postprocedure. CONCLUSION: Multicatheter high dose rate APBI is a safe and feasible procedure that can be carried out with minimal toxicity in Asian patients with breast volumes under 1,000 cc.

16.
Oncotarget ; 7(39): 64089-64099, 2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27577069

RESUMO

BACKGROUND: Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy. PATIENTS AND METHODS: In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. RESULTS: In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone. CONCLUSION: Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Indóis/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Antraciclinas/administração & dosagem , Biomarcadores Tumorais , Meios de Contraste , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Período Pré-Operatório , Sunitinibe , Resultado do Tratamento
17.
Oncotarget ; 7(34): 55155-55168, 2016 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-27487140

RESUMO

We studied the changes of intratumoral stromal proteins including THBS1, TNC, FN, SPARC and α-SMA, following neoadjuvant chemotherapy. The underlying mechanisms by which THBS1 and TNC regulated resistance to docetaxel were further studied using functional studies. 100 patients with newly diagnosed breast cancer were treated with alternating sequential doxorubicin and docetaxel. Immunohistochemistry (IHC) staining for stromal proteins was performed on pre- and post-treatment core biopsies respectively. THBS1 and TNC were further validated with IHC in an independent cohort of 31 patients. A high baseline combined expression score of the 5 stromal proteins predicted independently for poor progression-free (HRadjusted 2.22, 95% CI 1.06-4.64) and overall survival (HRadjusted 5.94, 95% CI 2.25-15.71). After 1-2 cycles of chemotherapy, increased expression of THBS1, TNC, FN, SPARC and α-SMA was seen in patients with subsequent pathological lymph node involvement at surgery. Increased expression of THBS1 and TNC compared to baseline was also seen in intrinsically resistant tumors, but not in sensitive ones. Both THBS1 and TNC-associated chemoresistance were confirmed in an independent validation cohort. Exogenous THBS1 and TNC protected MCF-7 cells against proliferation inhibition induced by docetaxel through activating integrin ß1/mTOR pathway. Thus, up-regulation of THBS1, TNC, FN, SPARC and α-SMA following neoadjuvant chemotherapy was associated with chemotherapy resistance in breast cancer patients. Functional studies showed THBS1 and TNC to mediate chemoresistance through the integrin ß1/mTOR pathway, suggesting that therapies targeting integrin ß1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Tenascina/fisiologia , Trombospondina 1/fisiologia , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Integrina beta1/fisiologia , Pessoa de Meia-Idade , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Tenascina/análise , Trombospondina 1/análise
19.
Oncotarget ; 7(3): 2532-44, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26565813

RESUMO

Statins purportedly exert anti-tumoral effects on breast cancer. However, the biologic mechanisms for these actions are not fully elucidated. The aims of this study were 1) to explore the effects of simvastatin on apoptosis, proliferation as well as PI3K/Akt/mTOR and MAPK/ERK pathway in a window-of-opportunity breast cancer trial; 2) to further confirm findings from the clinical trial by functional studies; 3) to explore the regulatory role of mevalonate pathway on the anti-tumoral effects of simvastatin. In clinical samples, simvastatin led to increase in cleaved caspase-3 (p = 0.002) and decreased trend for Ki67 (p = 0.245). Simvastatin markedly suppressed PI3K/Akt/mTOR signalling by activating PTEN (p = 0.005) and by dephosphorylating Akt (p = 0.002) and S6RP (p = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf (p = 0.018) and ERK1/2 (p = 0.002). In ER-positive (MCF-7, T47D) and ER-negative (MDA-MB-231, BT-549) breast cancer cells, simvastatin treatment consistently induced apoptosis and inhibited proliferation by deregulating caspase cascades and cell cycle proteins in a dose dependent manner. Concordantly, simvastatin strongly suppressed PI3K/Akt/mTOR pathway by enhancing PTEN expression and by further sequentially dephosphorylating downstream cascades including Akt, mTOR, p70S6K, S6RP and 4E-BP1. Furthermore, simvastatin significantly inhibited MAPK/ERK pathway by dephosphorylating sequential cascades such as c-Raf, MEK1/2 and ERK1/2. These simvastatin anti-tumoral effects were reversed by metabolic products of the mevalonate pathway, including mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These findings shed light on the biological and potential anti-tumoral effects of simvastatin in breast cancer.


Assuntos
Neoplasias da Mama/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácido Mevalônico/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sinvastatina/farmacologia , Adulto , Idoso , Apoptose , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Prognóstico , Estudos Prospectivos , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
20.
Nat Genet ; 47(11): 1341-5, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437033

RESUMO

Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.


Assuntos
Neoplasias da Mama/genética , Fibroadenoma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Mutação , Tumor Filoide/genética , Adolescente , Adulto , Idoso , Sequência de Bases , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Exoma/genética , Feminino , Fibroadenoma/metabolismo , Filaminas/genética , Filaminas/metabolismo , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Complexo Mediador/genética , Complexo Mediador/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tumor Filoide/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Adulto Jovem
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